Hypoxia-mimicked mitochondrial stress triggers APOBEC3A-mediated DNA damage via non-canonical innate immune activation

Here, we showed that cobalt chloride (CoCl2), a hypoxia-mimetic agent, potently induces the expression of the DNA cytidine deaminase APOBEC3A (A3A) in human THP-1 monocytic cells. A3A upregulation occurred in a dose-dependent manner, independently of type I interferon signalling, and was accompanied by increased double-strand DNA breaks.

Transcriptomic profiling revealed broad hypoxia-driven reprogramming, characterized by activation of the stress response and downregulation of mitochondrial signalling pathways. Mechanistically, cobalt chloride induced mitochondrial dysfunction, metabolic reprogramming, and cytosolic release of mitochondrial DNA (mtDNA). Cytosolic mtDNA was transcribed by RNA polymerase III into immunostimulatory RNA, which activated the RIG-I/TRAF6/NF-κB axis to drive A3A expression.